application of oxazolines in asymmetric aldol reaction...

193

Chapter 3

Application of Oxazolines

in

Asymmetric Aldol Reaction

and

Henry Reaction

194

Introduction


The controlled creation of new stereogenic centres is of paramount importance in

organic synthesis. Mainly three approaches are used to access chiral molecules, namely

resolution of stereoisomers, starting from enantiomerically pure isomers and by performing

asymmetric synthesis the through use of a chiral auxiliary, reagent or catalyst.

Use of asymmetric catalysts for accessing chirally pure organic compounds is by far

the most attractive and efficient option. The developments in the field of asymmetric catalysis

are inspired by the natural biochemical processes induced by biomolecules such as enzymes

and antibodies. Most of the early development was based on transition metal / chiral ligand

based asymmetric catalysis. Introduction of organic molecules capable of influencing the

basic organic reactions has ushered in the era of “organocatalysis” in modern chemistry. The

ability of organocatalyst to control the asymmetric transformation in the key step is attributed

mainly to supramolecular interactions, quite similar to the enzymes in the biochemical

reactions. Organocatalysts have advantages over the metal catalysed reactions, mainly it

reduces the use of metals which cause problems of disposal after completion of the reaction.

Elimination of the use of potentially toxic metal ion based catalysis in the wake of this

development goes well wih the advent of green chemistry and realization of the commitment

of the scientists towards the environmental cocerns.

The developments in the area are mostly focused on some of the carbon-carbon bond

forming asymmetric reactions such as aldol condensation and its varients, Michael reaction,

Baylis-Hillman reaction and Mannich reactions.1 In this chapter we will be focussing on

oganocatalytic application of chiral aminooxazolines in asymmetric aldol reaction,

preparation and charactersization of aminooxazolines have already been described in Chapter

2. Since this reaction has been developed, variety of organocatalysts have been desingned to

achieve good enantioselectivity in this organic transformation, most of them are prolione

derived organic molecules [Figure 1].

195

NH

O

OH

1

NHHN

HN

O S

HN

10

4

NH

NH

N

NN

32

HN

N

N

O

NH

5

NNHO

O

O

NH

Figure 1: Few examples of organocatalysts used for asymmetric aldol reaction

Hence, number of reports on aldol reaction proves the considerable attention on

application of organocatalysts in this carbon-carbon bond forming reaction. The major thurst

in this effort began with the pioneering work by Barbas, List and others when they utilized L-

proline to catalyse aldol reaction with excellent enantioselectivity.2

The L-proline 1 -catalyzed direct intermolecular asymmetric aldol reaction had not

been described by that time. Further, there were no asymmetric small-molecule aldol catalysts

that use an enamine mechanism. We initially studied the reaction of acetone with 4-

nitrobenzaldehyde in presence of L-proline 1 (30 mol %) in DMSO/acetone (4:1) at room

temperature for 4 h furnished aldol product (R)-8 in 68% yield and 76% ee [Scheme 1].2a

Variety of commercially available chiral amino acid have also been screened for this study

under the same condition. However, primary amino acids and acyclic secondary amino acids

failed to give significant amounts of the desired product.

Scheme 1: Asymmetric Aldol Reaction using L-Proline as Organocatalyst

It is widely accepted that the organocatalysed aldol reactions follow either acid

assisted enamine route [Scheme 2] or the base induced enol-enolate pathway [Scheme 3]. For

aldol reaction of unactivated ketones the enamine mechanism appears favourable, while the

base induced enol-enolate pathways is less likely due to the low acidity of the -protons.

196

Scheme 2: Mechanistic approach via Enamine intermediate

This mechanism involved several steps, including the nucleophilic attack of the amino

group (a), the dehydration of the carbinol amine intermediate (b), the deprotonation of the

iminium species (c), the carbon-carbon bond forming step (d), and both steps of the

hydrolysis of the iminium-aldol intermediate (e) and (f). The enantioselectivity can be

explained with a metal free version of a Zimmerman-Traxler type transition state.17 The

tricyclic hydrogen bonded framework provides for enantiofacial selectivity.

Scheme 3: Enol - Enolate pathway

Since these reports many applications of proline induced organocatalytic reactions

have been reported with varied degree of selectivity and mechanistic investigations. Besides

proline other chiral organic molecules based on thiourea,4 thiazolidine,5 cinchona alkaloids,6

peptides,7 cabohydrates8 etc. have been screened successfully as organocatalysts for

asymmetric reactions.

197

Recently an elegant combination of amino oxazoline and proline has been prepared

and tested for inducing chirality in intermolecular aldol reaction.9a These type of prolinamide-

oxazolines are amongst a series of modifications designed on the basic amino acid unit of

proline where a second chiral element has been introduced. Such derivatives with two chiral

units have been more selective as compared to some of the prolinamides prepared with achiral

amines.9b This series of prolinamide-oxazolines are neutral molecules in nature as the

carboxylic acid of proline is blocked by the amide group. Hansen et al. reported an interesting

approach for the preparation of polymer-supported proline via acrylic copolymerization.9c

These functionalized polymer systems have proven to be very efficient for asymmetric aldol

reactions and offer an advantageous recyclability. Cui and co-workers have also developed

chitosan immobilizecd proline10 and polyvinyl chloride supported proline11 as catalysts for

direct aldol reaction with good efficiency and performance. Inspiring from these reports, Cui

has utilized the ability of thiourea group being a weak Bronsted acid which able to activate

the electrophilic substrate via double-hydrogen bonding, to synthesize polymer supported

chiral organocatalyst 3 having incorporated L-proline and thiourea moieties in it [Figure 1]

and [Scheme 4].

Scheme 4: Asymmetric aldol reaction using polymer supported thiourea based organocatalyst 3

A cooperative catalyst system between a chiral transition-metal catalyst of the ligand

12 and achiral thiourea based Organocatalyst 11 was developed for highly diastereo- and

enantioselective aldol reaction of methyl -isocyanoacetate 13 and variety of aldehydes

[Scheme 5].4

198

CF3

NH

F3C NH

S

CF3

CF3

N

H

NHH

O

OH

O

HO

H

OMe

OMe

CN COOMeR

O

H+ R

NO

COOMe

11

Ln*

11 (20 mol%)DBU (20 mol%)

CoI2/Ln* (12) (10 mol%)

12

THF/1,4-dioxane (4:1)

23oC, 18h13 > 98% ee

> 20:1 dr

Scheme 5: Application of thiourea based achiral Organocatalyst 11 for asymmetric aldol reaction

For strong H-bonding to the carbon in isocyanides, an anion bonding interaction I

between thiourea and methyl -isocyanoacetate was established. The thiourea assisted

enolates would be capable of coordinating to a stereogenic metal centre in a more organised

fashion II [Scheme 6]. Based on spectroscopic investigations, the anion-bonding interaction

of the carbon atom of isocyanide and the N-H of the thiourea were evident.

Scheme 6: Mechanistic approach for the application of cooperative catalyst 11

Saccharide-derived bi-functional amine-thiourea 17 catalyst was developed by Ma et

al. and used in direct aldol condensation of trifluoroacetaldehyde methyl hemiacetal 14 with

benzaldehyde 15 to produce 16 with good stereoselectivity [Scheme 7].12

H C

HN

N

SR

R

NCOOMe

(I)

B

[MLn*]+

R'CHO

BH+

HC

H

NN

S

RR

N

O

MeO

MLn*

O

R'

(II)

BH+ B

H*

*

COOMe

R'-[MLn*]

-Thioureaproduct

199

Scheme 7: Saccharide-derived amine-thiourea organocatalyst 17 in aldol reaction

It was also noticed that nitrosobenzene could act as an electrophilic aminooxylating

reagent, inspring by this thought Hayashi and co-workers have examined the reaction between

a ketone and nitrosobenzene in the presence of chiral organocatalyst 1 or 3, and have

discovered the direct asymmetric -aminooxylation of ketones gave remarkably excellent

enantioselectivity up to 98% [Scheme 8].13

Scheme 8: Organocatalyzed asymmetric aminooxylation of ketones

A set of enantiopure thiazolidine-based organocatalysts have been by Schneider. In

particular, organocatalyst 20 exhibited the highest catalytic performance working in an

aqueous medium. It catalyzed the direct catalytic asymmetric intermolecular aldol reaction

between unmodified ketones and an aldehyde with excellent stereocontrol and furnished the

corresponding aldol products in up to 99% ee [Scheme 9].5

H

O

O

OOH

+

NH

O CH2Ph

Ph

OH

PhS

NH

20 (10 mol%)

Brine rt 120 h

21 99% ee15 7

20

Scheme 9: Application of thiazolidine-based organocatalyst 20 in asymmetric aldol reaction

Over the years, number of cinchona alkaloid and their derivatives have been

successfully applied in a wide diversity of organocatalytic reactions,14 acting as chiral-base,15

200

phase transfer16 and nucleophilic catalysts.17 Hence, due to their extraordinary catalytic

activity in organic transformations, Xiao and co-workers have developed a set of class of

chiral oragnocatalysts which incorporate the properties of well established proline and

cinchona alkaloid in single molecule and applied them for asymmetric aldol reaction which

resulted in to high degree of enantioselectivity [Scheme 10].18

Scheme 10: Cinchona alkaloid based organocatalyst 4 for aldol reaction

Guan et al. examined the application of bi-functional recoverable and reusable L-

Prolinamide oranocatalyst 5. This Organocatalyst was applied to the aldol reactions of

aromatic and heteroaromatic aldehydes with cyclic as well as acyclic ketones, and anti-aldol

product could be obtained with up to 1:99 syn:anti ratio and 98% ee. This type of

organocatalyzed asymmetric aldol reaction can be performed on a large-scale which offers the

possibility for applications in industry without affecting the enantioselectivity [Scheme 11].19

Scheme 11: Use of Prolinamide derived Organocatalyst 5 in aldol reaction

Interestingly, another class of carbohydrate based chiral organocatalysts 22 and 23

have also been developed to utilized the presence of the highly functionalized and having

several stereogenic centres which provides additional effect on stereoselectivity in aldol

reaction [Figure 2].8

Figure 2: Carbohydrate based oragnocatalysts 22 and 23

201

Many researchers have also studied isatin 24 as an acceptor of enolate in the

asymmetric organocatalyzed aldol reaction.7a,8b,20 Number of oragnocatalysts 25-28 have been

utilized for this purpose, some of them are listed below [Figure 3].21

Figure 3: List of Organocatalysts 25-28 used for aldol reaction of isatin 24

Using these oragnocatalysts for the asymmetric aldol reaction of isatin and acetone, 25

was found to be less effective giving only 2% ee for the R-isomeric product 29 and also

catalyst 26 was not at all exhibited stereoselectivity under the same condition. But the

catalysts derived by combination of thiourea and cinchona alkaloid derivatives, 27 and 28,

gave interesting results. Catalyst 27 having phenyl substituent at thiourea moiety resulted with

61% ee without changing stereochemistry of the chiral centre in aldol product whereas in case

of catalyst 28 having comparatively bulky 3,5-ditrifluormehhylphenyl substituent at thiourea

moiety exhibited same aldol product 29 with 85% ee [Scheme 12].21

Scheme 12: Organocatalyzed asymmetric aldol reaction of isatin 24

202

Asymmetric Henry Reaction

Among the C-C bond forming reactions, the nitroaldol (Henry) reaction is one of

the classical reactions in organic synthesis.22 The Henry reaction is a useful technique in the

area organic chemistry due to the synthetic utility of its corresponding products, as they can

be easily converted to other useful synthetic intermediates. These conversions include

subsequent dehydration to yield nitroalkenes, oxidation of the secondary alcohol to yield α-

nitro ketones, or reduction of the nitro group to yield β-amino alcohols. Many of these uses

have been exemplified in the syntheses of various pharmaceuticals including the β-blocker

(S)-propranolol,23 HIV protease inhibitor Amprenavir, and construction of the carbohydrate

subunit of the anthracycline class of antibiotics, L-Acosamine.24 It is also well known that

the nitroaldol products find increasing applications in the synthesis of natural products,

polyamino alcohols and polyhydroxylated amides. Generally, the nitroaldol reaction

involves the addition of a nitronate ion to a carbonyl compound. The nitronate ion can be

generated in situ by the deprotonation of a nitroalkane with an external base. The addition

is facilitated either by a Lewis acid catalyst or by a suitable bi-functional catalyst, while

the former activates the carbonyl partner, the latter works as a Lewis acid- Bronsted base

which activates and bring both reactants together.25

Many attempts to develop catalytic asymmetric nitroaldol reaction variants have

therefore been made.26 Out of the great number of metal-based catalysts, copper salts have

become the most widely used examples, because copper is a relatively cheap and low-toxicity

metal with excellent chelating properties.27

Recently, Gong has reported the synthesis of number of N,N-chiral ligands 30-37

derived from (-)-exo-bornylamine and also 38 from (+)-menthylamine [Figure 4]. They have

screened these ligands for Cu (II)-catalyzed asymmetric Henry reaction of variety of

aldehydes and nitromethane which exhibited excellent results in terms of conversion as well

as stereoselectivity [Scheme 13].28

Figure 4: Ligands used for Cu-catalyzed Asymmetric Henry reaction

203

Among these ligands, 30-34, 36 and 38 gave good results with enantioselectivities up

to 92%, whereas ligand 35 and 37 were not showing any stereoselectivity. All the ligands

produced Henry product 39 with S-isomeric form except ligand 38 where stereoselectivity

was inversed.

Scheme 13: Cu-catalyzed asymmetric Henry reaction

Variety of chiral oxazolinyl ligands have also contributed for metal catalyzed

asymmetric Henry reaction which showed excellent outcome for this reaction. A series of

novel C2-symmetric bis(thiazoline) ligands as well as bis(oxazoline) ligands have been

developed and screened for Cu-catalyzed asymmetric Henry reaction to exhibit good results.29

Another class of chiral oxazoline ligands have also been found to be successful for Cu-

catalyzed Henry reaction.30 Also certain Schiff base-Cu complexes were also reported to show

remarkable input for this nitroaldol reaction.31 Ligands derived from 1,2-diaminocyclohexane

framework were also developed to contribute for asymmetric Henry reaction with excellent

stereoselectivity.32

Considering these wide applications in organic transformations, we have screened our

aminooxazolines for asymmetric aldol reaction as well as asymmetric Henry reaction and the

results are encouraging which are well documented in this chapter.

204

Result and Discussion


Since the chiral amino oxazoline is a weak base we have screened number of

synthesized aminooxazolines 40-55 as oragnocatalysts for asymmetric aldol reaction with

sufficiently activated enolate acceptors. List of the aminooxazolines are shown in Figure 5.

NH

N

O

42

NH

N

O

41

NH2

N

O

40

Ph

O

NH

N

O

43

NH

N

O

NH

N

O

44 45

NH

N

O

46

NH

N

O

Br47

NH

N

O

NH

N

O

48 49

Figure 5: List of aminooxazolines 40-55 used as oragnocatalysts for asymmetric aldol reaction

205

With this concept we utilized 4-nitro benzaldehyde as the standard aldehyde and

scanned the conditions with number of amino oxazolines [Scheme 14] and [Table 1].

O2N

O

H 40-55 as organocatalysts

O

O2N

OH O

6

7

8

Scheme 14: Aminooxazoline catalyzed asymmetric aldol reaction

Recently polyethylene glycol was used as solvent for L-proline mediated aldol

reaction.33 Besides this we have also used other solvents [Table 1]. Reaction proceeded with

moderate results with PEG-400 and THF, while the configuration of the -hydroxy compound

8 was established as “R” by comparison of the observed optical rotation.

Table 1: Screening of amino oxazoline 47 (20 mol %) for

standard example of 4-nitro benzaldehyde and acetone (4

eq. Except for 3).

No Solvent Temp oC/ Ttime h

Yield/% % ee

(R)

1 PEG-400 30 / 24 79 16

2 PEG-400 5-8 / 24 61 51

3 Acetone 5-8 / 24 71 40

4 ACN 5-8 / 24 33 75

5 Toluene 5-8 / 24 16 91

6 THF 5-8 / 24 33 75

7 THF 5-8 / 72 48 71

206

The synthesized series of ligands were then scanned under the optimized condition of

THF as solvent for 72 h reaction time for 4-nitro benzaldehyde 6 and acetone 7. The results

are summarised in Table 2, in most cases the yield and selectivity was moderate to good. The

ligand with free –NH2 group (40) and –NHCOPh (41) were both ineffective to assist this

reaction, while derivatives prepared from tert-leucinol show good selectivity.

Table 2: Screening of amino oxazolines (20 mol %) for standard example of 4-nitro

benzaldehyde 6 and acetone 7 (4 eq.).

No Amino

oxazoline

Yield of

8

(%)

ee of

8-(R)

(%)

No Amino

oxazoline

Yield of

8

(%)

ee of

8-(R)

(%)

1 40 NR -- 9 49 59 39

2 41 NR -- 10 50 57 63

3 43 68 76 11 51 59 71

4 44 66 76 12 52 60 76

5 45 65 63 13 53 56 75

6 46 52 86 14 54 60 75

7 47 48 79 15 55 62 76

8 48 51 71

For all reactions: Solvent = THF; Reaction Temp = 5-8 oC; Time 72 h.

NR = no reaction.

The amino oxazoline 46 and 47 were found to show consistent results with both

good conversion and enantioselectivity. Hence, these were then investigated for a few

aromatic aldehydes attached with electron withdrawing substituents, results are

tabulated in Table 3.

207

Table 3: Screening of amines 46 and 47 for select examples.

-hydroxyketone

(R)

% Yield (% ee)

1

2

3

4

5

O2N

OH O

OH O

NO2

OH O

O2N

OH O

ClOH O

Br

with 46

54 (91)48 (79)

69 (91)72 (84)

73 (74)

68 (70)

47 (66)52 (61)

49 (84)

58 (57)

6 R = 4-NO2

56 R = 2-NO2

58 R = 3-NO2

60 R = 4-Cl

62 R = 4-Br

8

57

59

61

63

with 47No RC6H4CHO

We have also tried this system for the reaction of isatin 24 and acetone 7 in presence

of amino oxazoline 46 and the aldol product 29-(S) was isolated in moderate

enantioselectivity [Scheme 15].

Scheme 15: Application for aldol reaction of isatin 24 with acetone 7.

208

The major advantage of amino oxazolines is its high solubility in almost all routine

organic solvents, unlike proline. Since the reaction is assisted by a base and condition is

neutral (no acid additive is used) we propose that the reaction must be following enol-enolate

pathway. The enantioselectivity of the amino oxazolines for aldol reaction is mainly

controlled by the size and shape of the chiral substituent on the oxazoline ring and it is almost

independent of the group attached on the amino unit. However, the derivative 40 with primary

amino group as well as the benzoyl derivative 41 failed to catalyze this reaction. It is possible

that in the former the condensation of aldehyde with primary amine is a competing reaction

while the neutral nature of benzoyl derivative is not favoring the enol formation in the latter

case.

It is also noteworthy to mention that the acid labile amino oxazoline remains intact

after the reaction is complete (tlc), however, so far we have not made any attempts to recover

and recycle the catalyst.


We have also screened some of our chiral aminooxazolies as ligands for Cu-catalyzed

asymmetric Henry reaction of 4-nitrobenzaldehyde 6 and nitromethane to afford nitroaldol

product 64 with good conversion and modest enantioselectivity. We have screened 43, 44 and

46 as ligands and Cu salts to achieve the standard condition for this reaction [Scheme 16] and

[Table 4].

Scheme 16: Application of aminooxazolines in asymmetric Henry reaction

209

Table 4: Experimental parameters in search of standard conditon for Henry reaction

No. Cu Salt (mol%)

Ligand (mol %)

Additive (mol %)

Temperature (oC)

Time (h)

Yield of 64 (%)

ee of

64 (%)

1 Cu(OTf)2

(5%) 43 (10%) -- rt 72 46 Racemic

2 CuI (5%) 43 (10%) -- rt 72 41 Racemic

3 Cu(OAc)2.H2O

(5%) 43 (10%) -- rt 72 68 Racemic

4 Cu(OTf)2

(5%) 43 (10%) -- 5-8 72 trace --

5 Cu(OAc)2.H2O

(5%) 43 (10%) -- 5-8 72 63 25 (S)

6 CuCl2.H2O

(5%) 43 (10%) -- 5-8 72 NR --

7 Cu(OAc)2.H2O

(10%) 43 (10%) -- 5-8 72 62 21(S)

8 Cu(OAc)2.H2O

(5%) 43 (10%) DIPEA

(100 mol%) 5-8 72 81 Racemic

9 Cu(OAc)2.H2O

(5%) 44 (10%) -- 5-8 72 69 26 (S)

10 Cu(OAc)2.H2O

(5%) 46 (10%) -- 5-8 72 74 31 (S)

NR = no reaction. Stereochemistry was confirmed by the reportd optical rotation values in literature.

Initially we have used copper(II) triflate as a metal source and 43 as ligand in 1:2

proportion to make effective comlex to catalyse reaction of 4-nitrobenzaldehyde 6 and

nitromethane in dry ethanol at room temperature. Allthough the conversion was encouraging,

there was no selectivity observed in this reaction. Similar result was obtained with Cu (I)

iodide under the same experiental parameters. Cu(II) acetate salt gave the racemic product but

the yield was on the higher side which encouraged us to develop the condition using this

system. We tried this reaction with Cu(II) acetate (5 mol%) and ligand 43 (10 mol%) at lower

temperature around 5-8 oC, surprisingly it exhibited stereoselectivity of 25% ee for the

product (S)-64 in 72h. Under the same condition Cu(II) triflate and chloride were non-

productive at all. We have also perfomed a reaction with equimolar ammount of salt and

ligands which resulted with almost same conversion but slightly lower selectivity. Some

210

reports have prompted us to use DIPEA as a base with a intention to increase the

stereoselectivity of the product due to its bulky nature, but on the contrary it yielded the

product in racemic form with higher conversion. Hence we considered the experimental

condition shown in entry-5/Table 4 as a standard for the screening of other ligands. We have

screened two more ligands 44 and 46, earlier was having benzyl substituent at the oxazoline

ring and tert-butyl in the later. They both were equally effective as 43 which had iso-propyl

substituent at the oxazoline ring, resulted with 26% and 31% enantioselectivity respectively

for the (S)-64 without affecting the stereochemistry at the chiral centre.

Unfortunately, this catalyst system did not work for the other aromatic aldehydes.

211

Experimental Section

Reagents were purchased from Sigma-Aldrich Chemicals Limited, SD Fine, Sisco,

Qualigens, Avara Chemicals Limited etc. Tetrahydrofuran was refluxed over sodium

benzophenone-ketyl and freshly distilled prior to its use. Thin Layer Chromatography was

performed on Merck 60 F254 Aluminium coated plates. The spots were visualized under UV

light or with iodine vapour. All the compounds were purified by column chromatography

using Sisco Research Laboratory silica gel (60-120 mesh) and neutral alumina. All reactions

were carried out under an inert atmosphere (nitrogen) unless other conditions are specified.

NMR Spectra were recorded on 400 MHz Bruker Avance 400 Spectrometer (400 MHz for

1H-NMR & 100 MHz for 13C-NMR) with CDCl3 as solvent and TMS as internal standard.

Signal multiplicity is denoted as singlet (s), doublet (d), doublet of doublets (dd), triplet (t),

quartet (q) and multiplet (m). Mass spectra were recorded on Thermo-Fischer DSQ II

GCMS instrument. IR Spectra were recorded on a Perkin-Elmer FTIR RXI spectrometer as

KBr pallets. Optical rotations were measured on Jasco P-2000 polarimeter. Melting

points were recorded in Thiele’s tube using paraffin oil and are uncorrected. For the HPLC

analysis chiral L u x 5μ Amylase – 2, chiral Diacel OD-H column and Chiralpak IC column

were used on Shimadzu LC-20AD having UV-Vis detector.


Synthetic Procedures:

(R)-4-Hydroxy-4-(4-nitrophenyl)butan-2-one (8):

Amino oxazoline 46 (0.062 g, 0.20 mmol, 20 mol %) and acetone 7 (0.23 g, 4.0 mmol) was

stirred in dry THF at 5 – 8 oC for 30 min. 4-Nitrobenzaldehyde 6 (0.151 g, 1.0 mmol) was

added to the resulting solution and stirred at the same temperature for 72 hrs. Solvent was

evaporated under reduced pressure then 20 mL water was added to the crude mixture and

extracted 3 x 20 mL with ethylacetate, combined organic layer was dried over sodium

sulfate and solvent was evaporated on rotary evaporator. The crude material was purified by

column chromatography using 60 – 120 mesh silica gel and ethylacetate : petroleum ether as

eluent to afford aldol product 8 (R isomer) with (0.111g, 54%) light yellow solid

212

M.P. 58 oC (Lit.34 59 – 61 oC). = +35.30 (c 0.20, CHCl3). [Lit.35 = +35.2 (c 0.20,

CHCl3), 81% ee]

1H-NMR (400 MHz, CDCl3): δ 8.23 – 8.20 (m, 2H), 7.56 – 7.53 (dd, J = 2.0 & 6.4 Hz, 2H),

5.29 – 5.25 (m, 1H), 3.60 (d, J = 3.2 Hz, 1H), 2.92 – 2.80 (m, 2H), 2.23 (s, 3H).

IR (KBr): 3438, 3082, 2905, 1708, 1604, 1520, 134 cm-1

MS (EI): m/z (%) 208.73 (51), 190.85 (100), 173.70 (76), 152.05 (30), 104.47 (10), 90.81

(11), 76.83 (14), 57.84 (11).

Enantiomeric excess 91% determined by HPLC [Column: Lux 5μ Amylose-2; Solvent

system: Hexane/Iso-propanol (90:10); Flow rate: 1.0 mL/min; λmax = 254 nm; tR = 26.6 min

(minor, S isomer), tR = 31.7 min (major, R isomer)].

(S)-3-Hydroxy-3-(2-oxopropyl)indolin-2-one (29):

In a clean dry 25 mL flask, mixture of amino oxazoline 46 (0.063 g, 0.20 mmol, 20 mol %)

and acetone 7 (0.23 g, 4.08 mmol) was mixed in dry THF at 5 – 8 oC which then stirred for

30 min. To this clear solution, isatin 24 (0.15 g, 1.02 mmol) was added and stirred at the

same temperature for 72 hrs. Solvent was evaporated under reduced pressure then 20 mL

Water was added to the crude mixture and extracted 3 x 20 mL with ethylacetate, combined

organic layer was dried over sodium sulfate and solvent was evaporated on rotary

evaporator. The crude material was purified by Column Chromatography using 60 – 120

mesh silica gel; mixture of ethylacetate and petroleum ether as eluent to afford aldol product

29 (0.097 g, 46%) as off white solid

M.P. 166 – 168 oC (Lit.20 169 – 170 oC). = -21.11 (c 0.03, CH3OH)

[Lit.21 = -20.0 (c 0.03, CH3OH), 61% ee]

1H-NMR (400 MHz, DMSO): δ 10.09 (s, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.12 – 7.08 (t, J =

7.6 Hz, 1H), 6.87 – 6.83 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.92 (d, J = 1.6 Hz, 1H),

3.16 (d, J = 16.4 Hz, 1H), 2.98 (d, J = 16.4 Hz, 1H), 1.99 (s, 3H).

213

IR (KBr): 3362, 3260, 2358, 1718, 1621, 1472, 1365, 1077, 752 cm-1

MS (EI): m/z (%) 204.80 (100), 161.47 (80), 147.81 (92), 120.01 (43), 91.74 (19).

Enantiomeric excess 62% determined by HPLC [Column: Chiralcel OD-H; Solvent system:

Hexane/Iso-propanol (70:30); Flow rate: 1.0 mL/min; λmax = 254 nm; tR = 14.7 min (minor,

R isomer), tR = 20.9 min (major, S isomer).


In 25 mL flask, amino oxazoline 46 (0.062 g, 0.20 mmol, 20 mol %) and acetone 7 (0.23 g,

4.0 mmol) was stirred in dry THF at 5 – 8 oC for 30 min. To the resulting solution 2-

Nitrobenzaldehyde 56 (0.151 g, 1.0 mmol) was added and stirred at the same temperature for

72 hrs. Solvent was evaporated under reduced pressure then 20 mL water was added to the

crude mixture and extracted 3 x 20 mL with ethylacetate, combined organic layer was dried

over sodium sulfate and solvent was evaporated on rotary evaporator. The crude material

was purified by column chromatography using 60 – 120 mesh silica gel and ethylacetate :

petroleum ether as eluent to afford aldol product 57 (R isomer) (0.142 g, 69%) light yellow

solid.

M.P. 58 – 60 oC (Lit.36 59 - 61 oC). = -157.57 (c 0.3, CHCl3). [lit.37 = -141.0 (c

0.5, CHCl3), 91% ee]

IR (KBr): υ 3420, 3080, 2924, 1715, 1613, 1528, 1352 cm.-1

1H-NMR (400 MHz, CDCl3): δ 8.00 – 7.98 (dd, J = 1.2 & 8.4 Hz, 1H), 7.93 – 7.91 (dd, J =

1.6 & 8.0 Hz, 1H), 7.71 – 7.67 (m, 1H), 7.48 – 7.44 (m, 1H), 5.71 – 5.68 (dd, J = 2.0 & 8.2

Hz, 1H), 3.73 (bs, 1H), 3.19 – 3.14 (m, 1H), 2.78 – 2.71 (m, 1H), 2.26 (s, 3H).

IR (KBr): 3420, 3080, 2924, 1715, 1613, 1528, 1352 cm-1

MS (EI): m/z (%) 190.94 (M+-18, 5), 151.17 (34), 131.78 (77), 103.98 (100), 90.83 (26),

76.61 (40).



(minor, S isomer), tR = 40.4 min (major, R isomer)].

214


Mixture of amino oxazoline 46 (0.062 g, 0.20 mmol, 20 mol %) and acetone 7 (0.23 g, 4.0

mmol) was stirred in dry THF at 5 – 8 oC for 30 min. To the resulting solution 3-

Nitrobenzaldehyde 58 (0.151 g, 1.0 mmol) was added and stirred at the same temperature for

72 hrs. Solvent was evaporated under reduced pressure then 20 mL water was added to the

crude mixture and extracted 3 x 20 mL with ethylacetate, combined organic layer was dried

over sodium sulfate and solvent was evaporated on rotary evaporator. The crude material

was purified by column chromatography using 60 – 120 mesh silica gel and ethylacetate :

petroleum ether as eluent to afford aldol product 59 (R isomer) (0.154 g, 73%) off white

solid.

M.P. 50 oC (Lit.38 50 – 52 oC). = +63.13 (c 0.5 in CHCl3). [Lit.39 = +62.1 (c 0.35,

CHCl3), 87% ee]

1H-NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 8.15 – 8.13 (m, 1H), 7.72 (d, J = 7.6 Hz, 1H),

7.56 – 7.52 (m, 1H), 5.28 – 5.25 (m, 1H), 3.71 (bs, 1H), 2.91 – 2.89 (m, 2H), 2.24 (s, 3H).

IR (KBr): 3419, 3087, 2920, 1710, 1620, 1534, 1354 cm-1

MS (EI): m/z (%) 191.55 (M+-18, 100), 150.29 (77), 118.82 (28), 104.83 (74), 90.85 (39),

76.92 (89), 57.75 (66).



(major, R isomer), tR = 40.4 min (major, S isomer)].

(R)-4-(4-Chlorophenyl)-4-hydroxybutan-2-one (61):

In a clean dry 25 mL flask, mixture of amino oxazoline 46 (0.062 g, 0.20 mmol, 20 mol %)

and acetone 7 (0.23 g, 3.98 mmol) was stirred in dry THF at 5 – 8 oC for 30 min. To the

215

resulting solution 4-Chlorobenzaldehyde 60 (0.14 g, 0.996 mmol) was added and stirred at

the same temperature for 72 hrs. Solvent was evaporated under reduced pressure then 20 mL

water was added to the crude mixture and extracted 3 x 20 mL with ethylacetate, combined

organic layer was dried over sodium sulfate and solvent was evaporated on rotary

evaporator. The crude material was purified by column chromatography using 60 – 120 mesh

silica gel and ethylacetate : petroleum ether as eluent to afford aldol product 59 (R isomer)

(0.093 g, 47%) as white solid.

M.P. 50 oC (Lit.35 47 – 50 oC). = +55.17 (c 0.5, CHCl3). [Lit.37 = +62.7 (c 0.48,

CHCl3), 93% ee]

1H-NMR (400 MHz, CDCl3): δ 7.35 – 7.29 (m, 4H), 5.16 – 5.13 (m, 1H), 3.42 (d, J = 2.8

Hz, 1H), 2.90 – 2.78 (m, 2H), 2.22 (s, 3H).

IR (KBr): υ 3425, 3000, 2901, 1717, 1600, 1321, 571, 490 cm-1

MS (EI): m/z (%) 200 (8), 197.74 (39), 182.16 (10), 180.21 (14), 164.75 (13), 144.88 (31),

142.20 (15), 140.72 (100), 112.73 (26), 76.86 (57).



(major, R isomer), tR = 31.3 min (major, S isomer).]

(R)-4-(4-Bromophenyl)-4-hydroxybutan-2-one (63):

O

Br

OH

Mixture of amino oxazoline 46 (0.062 g, 0.20 mmol, 20 mol %) and acetone 7 (0.23 g, 4.0

mmol) was stirred in dry THF at 5 – 8 oC for 30 min. To the resulting solution 4-

Bromobenzaldehyde 62 (0.185 g, 1.0 mmol) was added and stirred at the same temperature

for 72 hrs. Solvent was evaporated under reduced pressure then 20 mL water was added to

the crude mixture and extracted 3 x 20 mL with ethylacetate, combined organic layer was

dried over sodium sulfate and solvent was evaporated on rotary evaporator. The crude

material was purified by column chromatography using 60 – 120 mesh silica gel and

ethylacetate : petroleum ether as eluent to afford aldol product 63 (R isomer) (0.120 g, 49%)

as off white solid

216

M.P. 58 oC (Lit.38 58 - 60 oC). = +26.61 (c 0.51 in CHCl3) [Lit.40 = +47 (c 0.5,

CHCl3), 95% ee]

1H-NMR (400 MHz, CDCl3): δ 7.50 – 7.48 (dd, J = 1.6 & 6.4 Hz, 2H), 7.27 – 7.24 (m, 2H),

5.15 – 5.12 (m, 1H), 3.40 (d, J = 3.2 Hz, 1H), 2.90 – 2.78 (m, 2H), 2.22 (s, 3H).

IR (KBr): 3247, 3067, 3027, 2844, 1718, 1605, 1322, 1077, 1051, 1028,

749, 687, 572, 544 cm-1

MS (EI): m/z (%) 244 (34), 242.04 (33), 226.11 (25), 225.21 (19), 186.98 (73), 185.00

(100), 158.99 (17), 156.96 (31), 76.84 (87).

Enantiomeric excess 84% determined by HPLC [Column: Chiralpak IC; Solvent system:


S isomer), tR = 32.4 min (major, R isomer)].

217


Synthetic Procedure:

(S)-2-Nitro-1-(4-nitrophenyl)ethanol (64):

In a clean dry 10 mL flask, Cu(OAc)2.H2O (0.010 g, 0.049 mmol, 5 mol%) was dissolved in

dry ethanol (3 mL) at room temperature then amino oxazoline 46 (0.020 g, 0.099 mmol, 10

mol %) was added to the same flask at 5-8 oC and stirred for 1 h at the same temperature. To

this green coloured catalyst solution, nitromethane (0.625 g, 9.93 mmol) was added drop wise

at the same temperature and stirred for additional 30 min. Then 4-nitrobenzaldehyde (0.150 g,

0.993 mmol) was added to the same flask and stirred for 72 h at 5-8 oC. Solvent was

evaporated under reduced pressure and resulting gummy crude product was purified by

Column Chromatography using 60-120 mesh silica gel; mixture of ethylacetate and

petroleum ether as eluent to afford Henry product 64 (0.157 g, 74%) as off white solid.

M.P. 80-82 oC (Lit.41 80-85 oC); = +12.01 (c 1.01, CH2Cl2) [Lit.31a = +35.9 (c

1.01, CH2Cl2), 92% ee]

1H-NMR (400 MHz, CDCl3): δ 8.28 – 8.26 (dd, J = 2.0 & 6.8 Hz, 2H), 7.63 (d, J = 8.8 Hz,

2H), 5.64 – 5.60 (m, 1H), 4.64 – 4.55 (m, 2H), 3.20 (d, J = 4.0 Hz, 1H).

IR (KBr): 3507, 2920, 2849, 1553, 1514, 1411, 1381, 1346, 1072, 849 cm-1

Enantiomeric excess 31% determined by HPLC [Column: Chiralcel OD-H; Solvent system:


R isomer), tR = 24.8 min (major, S isomer).

218

Spectral Data for Asymmetric Aldol Products

1H-NMR of the compound 8 (400 MHz, CDCl3)

1H-NMR of the compound 29 (400 MHz, DMSO)

219



220



221

HPLC Data for Aldol Products

Method For HPLC Analysis of the compound 8:

Solvent System: n-Hexane: Iso-propanol (90:10)

Flow rate: 1 mL/min.

Detector: UV-Vis (max – 254 nm)

Chiral Column: Lux 5μ Amylose-2

racemic

222





Chiral Column: Chiralcel OD-H

223











224





Chiral Column: Lux 5μ Amylose-2]





Chiral Column: Chiralpak IC

225

Spectral Data for Asymmetric Henry Product


226

HPLC Data for Henry Products



Flow rate: 0.8 mL/min.


Chiral Column: Chiralcel OD-H

racemic

227

Conclusion

A series of chiral amino oxazolines were synthesized and screened as organocatalysts

for asymmetric intermolecular aldol reaction between acetone and aromatic aldehydes.

The reaction works well with a range of aromatic aldehydes showing good to high

selectivity. The present new system of organocatalyst was effective for the asymmetric

aldol reaction for a wide range of aromatic aldehydes and isatin to accomplish the

asymmetric carbon-carbon bond forming reaction with a high selectivity of up to 91 %

ee.

We have also applied some of these aminooxazolines for copper catalyzed asymmetric

Henry reaction which exhibited moderate enatioinduction.

228

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